Publication Date:
2010-07-09
Description:
Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998662/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998662/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maunakea, Alika K -- Nagarajan, Raman P -- Bilenky, Mikhail -- Ballinger, Tracy J -- D'Souza, Cletus -- Fouse, Shaun D -- Johnson, Brett E -- Hong, Chibo -- Nielsen, Cydney -- Zhao, Yongjun -- Turecki, Gustavo -- Delaney, Allen -- Varhol, Richard -- Thiessen, Nina -- Shchors, Ksenya -- Heine, Vivi M -- Rowitch, David H -- Xing, Xiaoyun -- Fiore, Chris -- Schillebeeckx, Maximiliaan -- Jones, Steven J M -- Haussler, David -- Marra, Marco A -- Hirst, Martin -- Wang, Ting -- Costello, Joseph F -- U01 ES017154/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 8;466(7303):253-7. doi: 10.1038/nature09165.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20613842" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Brain/anatomy & histology/cytology/*metabolism
;
Carrier Proteins/genetics
;
Cell Line
;
Conserved Sequence/*genetics
;
CpG Islands/genetics
;
*DNA Methylation
;
DNA, Intergenic/genetics/metabolism
;
Frontal Lobe/metabolism
;
Gene Expression Regulation
;
Histones/genetics/metabolism
;
Humans
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Middle Aged
;
Nerve Tissue Proteins
;
Organ Specificity
;
Promoter Regions, Genetic/*genetics
;
Transcription, Genetic/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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